ClinVar Genomic variation as it relates to human health

Variant allele predicted to encode a truncated non-functional protein.

Variant summary: BRCA1 c.3084_3094del11 (p.Asn1029ArgfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes and c.3084_3094del11 has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Moller_2001, Judkins_2005, Couch_2015, Grindedal_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed this variant after 2014, including one expert panel and one consortium: all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3203_3213del11; This variant is associated with the following publications: (PMID: 16267036, 23199084, 24312913, 17574839, 11334729, 11720839, 12481264, 25452441, 29339979, 35216584, 34981296)

ClinVar contains an entry for this variant (Variation ID: 54768). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and triple-negative breast cancer (PMID: 17574839, 23199084, 25452441). It is commonly reported in individuals of Norwegian ancestry (PMID: 17574839, 23199084, 25452441). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1029Argfs*5) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

The c.3084_3094delTAATAACATTA pathogenic mutation (also known as3203del11), located in coding exon 9 of the BRCA1 gene, results from a deletion of 11 nucleotides between nucleotide positions 3084 and 3094, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

The BRCA1 c.3084_3094del11 variant is predicted to result in a frameshift and premature protein termination (p.Asn1029Argfs*5). In the literature this variant is also referred to as c.3203del11 or c.3084del11. This variant has been reported in individuals with breast and ovarian cancer (Moller et al. 2001. PubMed: 11334729; Moller et al. 2007. PubMed ID: 17574839; Heramb et al. 2018. PubMed ID: 29339979; Janavicius et al. 2010. PubMed ID: 23199084). Of note, this variant has commonly been reported in individuals of Norwegian descent (Moller et al. 2001. PubMed: 11334729; Janavicius et al. 2010. PubMed ID: 23199084; Heramb et al. 2018. PubMed ID: 29339979). This variant has not been reported in a large population database, indicating this variant is rare, and has been reported as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/54768/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.